title: Glaucocalyxin A and B-induced cell death is related to GSH perturbation in human leukemia HL-60 cells.
abstract: Glaucocalyxin (Gla) A-C are major ent-kauranoid diterpenoids isolated from Rabdosia japonica var. glaucocalyx, a plant used in Chinese traditional medicine as an antitumor and anti-inflammatory agent. The present investigation was carried out to observe whether cellular reduced glutathione (GSH) plays important roles in Gla -induced cytotoxicity. Among major ent-kauranoid diterpenoids isolated, Gla A and B dose-dependently decreased the growth of HL-60 cells with an IC50 of approximately 6.15 and 5.86 µM at 24 h, respectively. Both Gla A and B could induce apoptosis, G2/M-phase cycle arrest, DNA damage and the accumulation of reactive oxygen species (ROS) in HL-60 cells. Moreover, Gla A, B caused rapid decrease of the intracellular GSH content, while inhibition of cellular GSH synthesis by buthionine sulfoximine (BSO) augmented the induced cytotoxicity and apoptosis in HL-60 cells. On the other hand, the administration of GSH or GSH precursor N-acetyl-cysteine (NAC) could rescue Gla A, B-depleted cellular GSH, and abrogate the induced cytotoxicity, G2/M-phase cycle arrest, DNA damage and ROS accumulation in HL-60 cells. Furthermore, Gla A, B decreased the activity of the GSH-related enzymes including glutathione reductase (GR) and glutathione peroxidase (GPX). These data suggest that the intracellular GSH redox system plays important roles in regulating the Gla A, B-induced cytotoxicity on HL-60 cells.
authors.affiliation: College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
authors.forename: Wen Hua
authors.initials: WH
authors.lastname: Yang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yang Hu
authors.initials: YH
authors.lastname: Sima
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Jian Wen
authors.initials: JW
authors.lastname: Wang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D045786:Diterpenes, Kaurane; D017382:Reactive Oxygen Species; D019328:Buthionine Sulfoximine; C055124:glaucocalyxin A; C055125:glaucocalyxin B; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D005978:Glutathione; D000111:Acetylcysteine